Identification of PTPLAD1 as a Novel Tumor Suppressor and its Implication in Metastatic Colon Cancer Therapy

Abstract

Background: Colon cancer is one of the most common malignant cancers, and cancer metastasis always leads to a failure of clinical treatment. Although there have been many studies on the process of colon cancer progression, the detailed mechanism of colon cancer metastasis still remains unclear, and more effective drugs targeting colon cancer metastasis are urgently needed. This study aims to explore novel effectors involved in colon cancer metastasis and screen out potential targeted drug for colon cancer therapy.Methods: Mass spectrometry and bioinformatics analyses are performed to present the proteomics variation between two colon cancer cell lines with different invasion abilities. Boyden chamber invasion assay (in vitro) and experimental metastasis assay in mice (in vivo) are performed to explore the role of protein tyrosine phosphatase-like A domain containing 1 (PTPLAD1) in colon cancer metastasis. Western blotting and qRT-PCR assays are performed to analyze the expression of proteins and mRNA of related signaling cascades. Co-immunoprecipitation (Co-IP) and confocal assays are conducted to examine the proteins interacted with PTPLAD1. Chromatin-immunoprecipitation (ChIP) assay is fulfilled to evaluate the relationship of PTPLAD1 expression and histone H3K9 acetylation. Enzyme-linked immuno sorbent assay (ELISA) screening system are used to screen out the small molecular inhibitor that mimics the effect of PTPLAD1 on suppressing colon cancer metastasis.Results: Our results identify that PTPLAD1 is significantly downregulated in the highly invasive cell lines, and PTPLAD1 suppresses colon cancer metastasis by interacting with prohibitin (PHB) and prohibiting the activation of PHB/C-Raf1 (Raf)/ extracellular signal-regulated kinase (ERK)/Snail signaling pathway. Moreover, the expression of PTPLAD1 is modulated through the acetylation of histone H3K9. Besides, we identify a small molecule named avobenzone, once used to protect skin from ultraviolet damage, that can disrupt the interaction of PHB and Raf, significantly abrogate the activation of downstream signaling cascades and prohibit colon cancer metastasis.Conclusions: Collectively, our study not only identifies PTPLAD1 as a novel tumor suppressor and clarifies its role in suppressing colon cancer metastasis, but also provides a potential targeted drug for metastatic colon cancer therapy.

Potential Effects of Akkermansia Muciniphila in Aging and Aging-Related Diseases: Current Evidence and Perspectives

“…Beta-Carotene is thought to modulate telomerase activity in old age [43]. Of note, we found that almost all these antiaging plant supplements increased the abundance of A. muciniphila to varying degrees [44][45][46][47]. However, it has not been possible to determine whether the anti-aging effects of these plant supplements are associated with an increased abundance of A. muciniphila.…”